Project Summary The brain?s ability to extract relevant information and filter out distractors from a complex sound environment is critical to perceive physiologically relevant sounds such as language. This ability is often deficient in Autism spectrum disorder (ASD) and affects the ability of patients to understand and interact with the world around them. Specifically, ASD patients have reduced response to speech, hypersensitivity to normal stimuli, and are easily overwhelmed in noisy environments. These sensory processing deficits could be attributed to changes in the neuronal circuitry that affect how sounds are integrated to perceive relevant stimuli. In humans, integration of individual sounds is dependent on the synchrony of the components? onset within a 30-ms window, and accurately integrating harmonic sounds in particular is critical for our perception of language. However, the neuronal circuits that underlie complex sound integration in the auditory cortex and how they contribute to sensory deficits in ASD are unclear. To address this gap in knowledge, I will identify the neuronal circuit mechanisms underlying the temporal integration of harmonic sounds in the auditory cortex. In addition, I will use a mouse model of Angelman syndrome (AS, Ube3am-/p+) to investigate how these circuits contribute to sensory processing and speech discrimination deficits. I hypothesize that the temporal integration window for binding of harmonic sounds, and thus the ability to integrate information originating from the same source, is controlled by the activity of inhibitory neurons in cortical circuits. In addition, I expect that an alteration of inhibition in AS mice changes the time window for integration of harmonic sounds, which contributes to sensory processing deficits in ASD patients. In this proposal I aim to 1) Compare the perceptual window of harmonics between wild-type (WT) and AS mice using a behavioral discrimination task, 2) Determine the neuronal mechanism of harmonics integration in WT and AS mice using in vivo two-photon calcium imaging, and 3) Identify the culprits underlying AS phenotypes by rescuing Ube3a expression in specific cell types. Overall, this study will contribute to our knowledge of how harmonic sounds are integrated in the auditory cortex, which has valuable implications for our understanding of how we process speech. In addition, identifying cell types that contribute to sensory processing deficits in neurodevelopmental disorders could identify therapeutic targets to improve the lives of patients.